Selective estrogen receptors modulators (SERMs), such as tamoxifen and raloxifene, have been shown to be neuroprotective, but the mechanisms of neuroprotection are unknown. The underlying hypothesis of this application is that raloxifene is a neuroprotective in ALS by activating the estrogen receptor alpha (ER??- dependent mitochondrial unfolded protein response (UPRmt). This hypothesis stems from our recent findings in the SOD1-G93A mouse model of familial ALS. In this mouse, we found activation of the ER?-mediated axis of the UPRmt. We reported that, upon accumulation of misfolded SOD1 in the mitochondrial intermembrane space (IMS), the ER? signaling pathway is activated and promotes the expression of the IMS protease OMI, subunits of the 26S proteasome and the nuclear respiratory factor 1 (NRF1), a direct target of ER?, which in turn stimulates the transcription of several mitochondrial proteins. We recently studied this pathway in the SOD1- G93A mice and found that females activate the UPRmt more potently than males and this correlates with the longer survival in females. Further, we showed that accumulation of misfolded SOD1-G93A in ER??knockout mice failed to activate the UPRmt. Taken together, these results indicate that the neuroprotective effect of the UPRmt requires ER?-mediated activation of three major targets, OMI, NRF1 and the 26S proteasome. We tested whether estrogen, tamoxifen, and raloxifene differentially induced the UPRmt specifically in the spinal cord. We found that raloxifene is a potent inducer of NRF1 and the proteasome in the spinal cord, while tamoxifen or estrogen are not. We also performed preliminary pilot studies on the effect of chronic raloxifene administration to SOD1-G93A mice and found that it stimulates UPRmt and delays disease progression. Based on these exciting results, in this exploratory application we will test the hypothesis that raloxifene may represent a novel therapeutic approach against ALS by maintaining the activation of the UPRmt. We propose two specific aims. Aim 1: will systematically test the protective effects of different doses of raloxifene in the SOD1-G93A mouse model of ALS, starting at presymptomatic and symptomatic disease stages. Aim 2: will validate that the molecular targets have been hit upon treatment with raloxifene, by assessing the activation of the ER? axis of the UPRmt and its transcriptional effects in the spinal cord of SOD1-G93A mice.